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Visible-light-mediated α-phosphorylation of N -aryl
tertiary amines through the formation of
electron-donor–acceptor complexes: synthetic and
mechanistic studies
Valentin Quint, Nourhène Chouchène, Moheddine Askri, Jacques Lalevée,
Annie-Claude Gaumont, Sami Lakhdar
To cite this version:
Valentin Quint, Nourhène Chouchène, Moheddine Askri, Jacques Lalevée, Annie-Claude Gaumont, et al.. Visible-light-mediated α-phosphorylation of N -aryl tertiary amines through the formation of electron-donor–acceptor complexes: synthetic and mechanistic studies. Organic Chemistry Frontiers, Royal Society of Chemistry, 2019, 6 (1), pp.41-44. �10.1039/C8QO00985F�. �hal-03101165�
Visible–light–mediated –phosphorylation of N–aryl tertiary amines through the formation of electron–donor–acceptor Complexes: synthetic and mechanistic studies
Valentin Quint,a Nourhène Chouchène,b Moheddine Askri,b Jacques Lalevée,c Annie-Claude
Gaumont,a and Sami Lakhdar*a
This work describes an efficient –phosphorylation of a wide variety of N–aryl tertiary amines under mild conditions. It consists of a simple combination of amines (electron donors) with N-ethoxy-2-methylpyridinium tetrafluoroborate (electron acceptor) in the presence of P(V)–H compounds under visible light irradition. Physical organic investigations support the formation of an electron–donor–acceptor complex (amine/pyridinium ion) as a key intermediate.
Introduction
The direct and efficient –C(sp3)–H functionalization of tertiary amines into carbon–
phosphorus bonds is a challenging organic transformation that attracted much attention during the last few decades.1 This is obviously due to the potential biological
activities of -aminophosphonates and -aminophosphonic acids in numerous natural and pharmaceutical compounds.2
Based on the use of the well-known cross-dehydrogenative coupling (CDC) technology3
between an sp3C–H bond adjacent to a nitrogen atom of N–aryl amines 1 and an H–P
bond, various approaches have been reported for the synthesis of -phophorylated amines 3. As depicted in Scheme 1 (upper part), these methods rely on the use of transition metal catalysts (method a),1a–c,1i organic– or organometallic–based
photocatalysts (method b)1d–j or the employment of polyhalomethanes under blue light
irradiations.1k It should be mentioned that Zeitler et al. have recently reported a visible
light photocatalyst free approach for –functionalization of tertiary amines, which has successfully been applied for carbon-carbon as well as carbon–phosphorus bonds (method c).1k Detailed mechanistic studies of these different approaches revealed the
intermediacy of an iminium ion, which can then be intercepted with the phosphorus nucleophiles to furnish the desired -phosphonated amines.
Although the efficiency of these methods, they have mainly been restricted to tetrahydroisoquinolines (THIQ) as tertiary amines and to H-phosphonates as phosphorus nucleophiles. For instance, secondary phosphine oxides 2 (R1R2P(O)H) are
not compatible with many of the reaction conditions outlined above due to their low stability of in the presence of oxidants.4 In order to solve this synthetic issue and to
provide an efficient approach for the formation of C–P bonds between N–aryl tertiary amines and secondary phosphine oxides, we hypothesized the working reaction mechanism depicted in Scheme 1. It consists of the association of an N–aryl amine 1
with N-ethoxy-2-methylpyridinium tetrafluoroborate 4,5 which is a well-known
electron-acceptor cation, to form an electron-donor-acceptor (EDA) complex 5.6
Scheme 1. a) Common approaches for the phosphonylation of tertiary amines. b) Our
working hypothesis for the generation of iminium ions through the association of N– aryl tertiary amines with N-ethoxy-2-methylpyridinium tetrafluoroborate under visible light irradiation. TM: transition metal catalysts; PC: photocatalysts.
Upon visible light irradiation, a single electron transfer (SET) between both components should take place to give rise to the formation the ethoxy radical (EtO⚫, 6) along with
the tertiary amine radical cation 7 (Scheme 1). Because of the very weak bond dissociation energy of the C–H bond of the radical cation (BDE ≈ 42 kcal/mol),7 a fast
hydrogen atom abstraction (HAT) occurs with EtO⚫ to form the corresponding iminium ion 8, which can be intercepted by secondary phosphine oxides (Scheme 1).
Results and discussion
To test this hypothesis, we started our investigation by combining N,N–dimethylaniline
1a (1 equiv.) with diphenylphosphine oxide 2a (1 equiv.) in the presence of
N-ethoxy-2-methylpyridinium tetrafluoroborate 4 (1. equiv.) as an oxidant and NaHCO3 (1.2
conversion of 3a has been attained by 31P NMR after 24h (Table 1, entry 1, 78%). Using
sodium acetate as a base (entry 2), or carrying out the reaction in the absence of a base (entry 3), gave modest 63% and 47% conversions, respectively, thus, showing the efficiency of NaHCO3 as a base in the reaction.
Table 1. Optimization of reaction conditions.a
Entry Solvent Yield of 3a, %b
1 DMF 78 2 DMF 63c 3 DMF 47d 4 CH3CN 66 5 DMSO 75 6 MeOH 57 7 DMF 74e 8 DMF 93f 9 DMF 82g 10 DMF 0h 11 DMF 0i
a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 4 (0.5 mmol), NaHCO3 (0.6 mmol), solvent (4 mL), 24h. b NMR yields are determined from 31P NMR spectroscopy, using
tri-n-octylphosphine oxide as an internal standard. c Base: NaOAc. d No base. e Irradiation with white LEDs. f 1a (0.5 mmol), 2a (1 mmol), 4 (0.6 mmol), NaHCO3 (0.6 mmol), solvent (4 mL), 24h. g
1a (1 mmol), 2a (0.5 mmol), 4 (0.6 mmol), NaHCO3 (0.6 mmol), solvent (4 mL), 24h. h The
reaction is protected from external light with foil and heated at 40 °C to reproduce the heat caused by the LED lamp. i No oxidant.
Although good results have been observed with acetonitrile (entry 4, 66%) and DMSO (entry 5, 75%), the conversion dropped in polar and protic solvents such as MeOH (entry 6, 57%). We furthermore tested the stoichiometry of the reactants and observed that using two equivalents of 2a with respect to 1a furnished 93% of 3a (entry 8), whereas 82% of conversion was observed when an excess of 1a was used (entry 9). We
finally confirmed the necessity of light (entry 10) and oxidant (entry 11) as no reaction took place in their absence.
With the optimized reaction conditions in hand, we next explored the scope of the process by using different N–aryl amines and secondary phosphine oxides.
As shown in Figure 1, various ring-substituted N,N-dimethylanilines carrying electron donor substituents 1b,d can be phosphorylated in excellent yields (81-87%). The reaction proceeds also well with N,N-dimethyl anilines having fluoro– or bromo– groups at the para position of the aromatic ring 1e (71%) and 1f (68%), respectively. Interestingly, apart from the N,N–dimethylanilines, the phosphorylation worked efficiently with N,N-diethylaniline 1g (76%) and THIQ 1h (91%).
Diarylphosphine oxides bearing different groups such as t-Bu (2i), OMe (2j), CF3 (2k) at
para position of aromatic rings were all applicable to the coupling with 72–93% yields. The reaction of the sterically hindered di(o-tolyl)phosphine (2l) with 1a successfully afforded the desired adduct 3l in 74% yield. Finally, the reaction of 1a with H– diethylphosphite gave the corresponding phosphonated adduct 3m in 77%.
Figure 1. Scope of the reaction.
Reaction conditions: 1 (0.5 mmol), 2 (1 mmol), 4 (0.6 mmol), NaHCO3 (0.6 mmol), DMF
(4 mL) were irradiated with blue LEDs (5W) for 24h.
Having investigated the scope of the photoreaction with different N–aryl amines and secondary phosphine oxides, we next turned our attention to study the mechanism of this phosphorylation reaction. As shown in Figure 2, while UV-Vis spectra of 1a (blue) and 4 (red) in DMF are silent in the visible region, the spectrum of a mixture of both components (green) shows a bathochromic displacement above 400 nm. This new intermediate has been assigned to the formation of an EDA complex 5.6 We next
employed Job’s method of continuous variations to determine the molar donor/acceptor ratio, which has been found to be 1:1 in DMF at 20 °C (Figure 3). Furthermore, an association constant KEDA of 2.7 M–1 has been determined
photometrically in DMF by using the Benesi–Hildebrand method (See ESI). This constant is in good agreement with those reported by Melchiorre for the EDA
complexes formed upon association of substituted 1 H–indoles with electron accepting benzyl and phenacyl bromides.6f
Figure 2: UV-Vis spectra of N-ethoxy-2-methylpyridinium tetrafluoroborate 4 ([4] = 5 × 10–2 M) (red); (b) N,N–dimethylaniline 1a ([1a] = 5 × 10–2 M) (blue); a mixture of 1a and
4 (green) in DMF at 20°C.
Figure 3. Job’s plot for the association of 1a and 4 in DMF at 20 °C.
Light on/off experiments of the reaction of 1a with 2a under the optimized reaction conditions have been conducted and revealed an interruption of the reaction progress in the absence of light, and recuperation of reactivity upon further illumination (See Figure S5, ESI). Furthermore, a quantum yield (ɸ) of 0.28 was determined, indicating that a radical chain process is presumably not operative.8
To characterize the nature of the radical species involved in this reaction, a spin trap EPR experiment was undertaken in the presence of N-tert-Butyl-α-phenylnitrone (PBN)
9 as a spin trap. Interesting the ethoxy-PBN adduct 10 was detected and the
determined hyperfine coupling constants (aN = 13.7 G and aH = 1.9 G) was found to be
Figure 4. EPR spectra of spin adduct 10 generated in toluene from the reaction of N,N–
dimethylaniline 1a (1 × 10-2 M) with N-ethoxy-2-methylpyridinium tetrafluoroborate 4
(1 × 10-2 M) in the presence of PBN 9 (1 × 10-2 M) at 20°C.
Finally, in order to elucidate the intermediacy of the iminium ion 8 derived from N,N– dimethylaniline 1a, we recorded 1H NMR spectrum of the reaction of 1a with 4 in
CD3CN. However, because of its high electrophilicity,9 it reacted with the generated
ethanol to form the adduct 11 (Scheme 2). Interestingly, when THIQ (1h) was used instead of 1a, the corresponding iminium ion was detected by NMR spectroscopy. Based on these physical organic investigations, a reaction mechanism is proposed (Scheme 2). The reaction starts with the association of the amine (electron donor) 1 with the pyridinium salt 4 to form an EDA complex 5. After visible light irradiation, a single electron transfer takes place to generate the ethoxy radical (6) and the aminium radical cation 7. A fast hydrogen atom abstraction takes place to generate the iminium ion 8 that reacts with the diarylphosphine oxide (P(III) tautomer) to form the phosphonium ion 12. The deprotonation of the latter with a base yields the desired product 3.
Scheme 2. Proposed reaction mechanism.
Conclusion
In conclusion, we have developed a metal–free, visible–light– induced method for the phosphorylation of N–aryl amines 1 with secondary phosphine oxides 2. The reaction proceeds under mild, catalyst-free conditions. Key to the success of the reaction was the formation of EDA complexes between the amines 1 and the electron-deficient pyridinium 4. The proposed reaction mechanism was supported by detailed mechanistic investigations, including spectrophotometry, NMR spectroscopy and EPR spectroscopy. We anticipate that this operationally simple approach should be amenable with other nucleophiles to synthesize various -functionalized amines.
Acknowledgements
The authors thank the CNRS, Normandie Université, INSA Rouen, and Labex Synorg (ANR-11-LABX-0029) for financial support. V.Q. is grateful to the “Ministère de l’enseignement supérieur et de la recherche“ for a fellowship. N.Ch. thanks the University of Monastir for a Scholarship.
Notes and references
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